The principal scientific goal for the proposed research is to develop efficient methodology for the synthesis of polycyclic cycloheptanoid ring systems many of which have considerable therapeutic potential. In particular, the fused ring structures analogous to those found in the biologically active frondosin family of natural products as well as liphagal, a structurally related compound, are targeted. All five of the known frondosins (A-E) are novel sesquiterpene hydroquinone derivatives, which have been found to be antagonists of interleukin-8 (IL-8) and inhibitors of protein kinase C (PKC) in the low micromolar range. Protein kinase C has been shown to play a major role in cellular signal transduction and IL-8, a neutrophil-activating peptide, is produced by several cell types in response to inflammation. Interleukin-8 has also been implicated in tumor progression and metastasis in several human cancers, and it is involved in chemoattraction, neovascularization and stimulation of HIV-1 replication in both T-lymphocytes and macrophages. Indeed, it has been demonstrated that compounds capable of reversing the binding of IL-8 also inhibit HIV-1 replication. Liphagal is a specific inhibitor of the phosphatidyl-3-kinase (PI3K) and it was found to exhibit significant in vitro cytotoxicity against several human tumor lines. Thus, the molecular targets pursued in the proposed work hold considerable potential as valuable lead compounds for the development of novel agents to treat several acute and chronic inflammatory diseases, and they may prove useful as therapeutic agents against cancer and AIDS. The specific goals for the proposed research are: (A) to extend the scope of a tandem cyclization-Claisen rearrangement process, developed in the PI's lab, for the enantioselective synthesis of novel fused cycloheptanoid ring systems;(B) to apply these strategies for the efficient total syntheses of frondosins A, B, D, E and liphagal in optically active form, and (C) to provide samples of synthetic intermediates and novel analogs of these natural products for biological testing, which will be done at the NCI natural products chemistry group (Molecular Targets Development Program). It is anticipated that the chemistry described in this proposal will ultimately prove useful as a general method to access a number of cycloheptanoid natural products and may result in a number of novel structures possessing significant biological activity. PUBLIC HEALTH RELEVANCE: The molecular targets pursued in the proposed work hold considerable potential as lead compounds for the development of novel medicinal agents for the treatment of treat several acute and chronic inflammatory diseases, as well as cancer and AIDS.